CN113024449A - Metal-containing high-efficiency cationic antitumor drug and preparation method and application thereof - Google Patents

Metal-containing high-efficiency cationic antitumor drug and preparation method and application thereof Download PDF

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CN113024449A
CN113024449A CN202110289014.XA CN202110289014A CN113024449A CN 113024449 A CN113024449 A CN 113024449A CN 202110289014 A CN202110289014 A CN 202110289014A CN 113024449 A CN113024449 A CN 113024449A
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尤业字
聂旋
张泽
夏磊
陈�光
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract

The invention relates to a metal-containing high-efficiency cationic antitumor drug, and a preparation method and application thereof. Specifically, the invention relates to metal cation compounds of formula I wherein M is a divalent metal, n is an integer from 1 to 10, X is independently selected from O, S and NH, and R is a hydrophobic chain hydrocarbyl group. The metal cation medicament has broad-spectrum anticancer property, does not generate drug resistance, reduces toxic and side effects while improving the antitumor effect, and can treat tumors without a carrier. In addition, the amphiphilic micromolecule has a simple structure, can play a role without entering cells, cannot generate drug resistance, and can inhibit tumor metastasis.

Description

Metal-containing high-efficiency cationic antitumor drug and preparation method and application thereof
Technical Field
The invention belongs to the field of biological materials, and particularly relates to a cationic antitumor drug, and a preparation method and application thereof.
Background
Cancer is an important factor threatening the health of human life. Due to the special microenvironment of cancer, effective means for prevention and control of cancer still lack, and cancer has great influence on the life health and social economy of people. At present, the main problems of chemotherapy are that tumor cells cannot be accurately and selectively killed, and the toxic and side effects are large; chemotherapeutic drugs flow through the whole body through blood circulation and are less enriched at tumor sites; the chemotherapy medicament is easy to generate multi-drug resistance, namely, the chemotherapy medicament has a certain effect in the initial stage of tumor treatment, and after multiple times of treatment, tumor cells are easy to generate drug resistance, so that the sensitivity of the chemotherapy medicament is reduced. The main reason is that the conventional chemotherapeutic drugs must enter the cells to act with intracellular biomacromolecules to inhibit the growth of cancer cells and kill the cancer cells. However, cancer cells have a good mechanism for pumping these drugs out of the cell, and thus have strong resistance. To solve the problems, a novel and efficient cancer cell targeting mechanism must be developed to reduce toxic and side effects; develops a mechanism different from the common chemotherapy drug for killing cancer cells, and constructs the anti-tumor nano-drug without drug resistance and with high efficiency. The research in the aspect has very good academic research value and also has very good social requirements.
Disclosure of Invention
In order to solve the defects of the existing antitumor drugs, the invention provides an organic metal complex which has specific binding interaction with the phosphatidylserine on the surface of the tumor cell membrane and can be selectively bound with the phosphatidylserine on the cancer cell membrane so as to realize the accurate targeting of the cancer cell; secondly, an organic molecular ligand with a strong cell membrane breaking effect is constructed, and the metal nano-drug is formed through self-assembly to realize the efficient cell membrane breaking effect on cancer cells, so that the cancer cells are apoptotic and do not need to enter the cancer cells.
The metal cation medicament has the following advantages: 1) it can effectively and accurately kill tumor cells; 2) the tumor killing mechanism is different from that of common chemotherapeutic drugs, namely the tumor killing mechanism does not enter cells, so that drug resistance cannot be generated; 3) it can destroy tumor tissue cells, so that it can permeate into tumor tissue to kill cancer cells effectively.
The invention aims to provide a metal cation anti-tumor medicament.
The invention also aims to provide a preparation method of the metal cation anti-tumor medicament.
The invention also aims to provide application of the metal cation anti-tumor medicament.
The purpose of the invention is realized by the following technical scheme.
The invention provides a metal cation compound of formula I,
Figure BDA0002981678550000021
wherein
M is a divalent metal;
n is an integer of 1 to 10;
x is independently selected from O, S and NH; and is
R is a hydrophobic chain hydrocarbon group.
The metal cation compounds of formula I consist of a hydrophobic tail and a hydrophilic head, wherein the hydrophilic head is formed by the complexation of a dimethylaminopyridine amine moiety with a divalent metal ion.
In some embodiments, the divalent metal M comprises Zn, Ni, Cu, Fe, and Co.
In some embodiments, n is an integer from 1 to 5 (e.g., 1, 2, 3, 4, and 5), preferably n is 2.
In some embodiments, R is C1-20Chain hydrocarbon radicals, e.g. C1-16Chain hydrocarbon radicals, e.g. C1-12Chain hydrocarbon radicals, e.g. C1-6A chain hydrocarbon group.
In some embodiments, R is C1-20Alkyl or alkenyl radicals, e.g. C1-16Alkyl or alkenyl radicals, e.g. C1-12Alkyl or alkenyl radicals, e.g. C1-6An alkyl or alkenyl group.
In some embodiments, R is selected from:
Figure BDA0002981678550000031
the present invention provides a process for preparing a metal cation compound of formula I, the process comprising:
(1) reacting acryloyl chloride with a hydrophobic structure (alcohol, amine, mercaptan) of the formula R-X-H in an organic solvent to obtain a hydrophobic structure with conjugated double bonds of the formula II
Figure BDA0002981678550000032
Wherein R and X are as defined above;
(2) the compound of formula II and the compound of formula III (dimethylamino pyridylamine structure with amino) are subjected to Michael addition in an organic solvent to obtain the compound of formula IV
Figure BDA0002981678550000033
Wherein n is an integer from 1 to 10;
(3) reacting the compound of formula IV with a divalent metal salt in an organic solvent to obtain the metal cation compound of formula I.
The synthesis of a specific metal cation compound of formula I is shown in figure 1.
In some embodiments, the hydrophobic structure of formula R-X-H comprises the following structure:
Figure BDA0002981678550000041
in some embodiments, the structure with conjugated double bonds of formula II includes the following structures:
Figure BDA0002981678550000042
in some embodiments, n is an integer from 1 to 5 (e.g., 1, 2, 3, 4, and 5), preferably n is 2.
In some embodiments, the divalent metal salt includes zinc salts, nickel salts, copper salts, iron salts, and cobalt salts, preferably zinc nitrate, zinc sulfate, zinc acetate, zinc chloride, zinc bromide, nickel nitrate, nickel sulfate, nickel acetate, nickel chloride, nickel bromide, cobalt nitrate, cobalt sulfate, cobalt acetate, cobalt chloride, cobalt bromide, copper nitrate, copper sulfate, copper acetate, ferrous nitrate, ferrous sulfate, ferrous acetate, and any combination thereof. Preferred divalent metal salts are nickel nitrate, zinc nitrate and cobalt nitrate.
In some embodiments, the organic solvent in steps (1) to (3) is independently selected from the group consisting of dimethylsulfoxide, N-dimethylformamide, dichloromethane, trichloromethane, tetrahydrofuran, methanol, ethanol, acetonitrile, and any combination thereof.
In some embodiments, the reaction in step (1) is carried out with triethylamine as an acid-binding agent. In some embodiments, the reaction temperature in step (1) is 20-30 ℃ and the reaction time is 4 to 12 hours.
In some embodiments, the reaction in step (2) is carried out in the presence of triethylamine and under an inert atmosphere. In some embodiments, the reaction temperature in step (2) is 90-110 ℃ and the reaction time is 24 hours to 48 hours.
In some embodiments, the reaction temperature in step (3) is 20-30 ℃ and the reaction time is 4 to 12 hours.
The invention has the advantages of
In normal cells, phosphatidylserine is located in the intracellular membrane, and when apoptosis of the cells occurs, the phosphatidylserine located in the intracellular membrane is everted to cause a series of physiological changes. When cells cancerate, phosphatidylserine positioned in the cell inner membrane can be transferred to the cell outer membrane, thereby promoting the growth and the transfer of tumors and inhibiting the immune microenvironment in vivo. Therefore, the metal cation compound designed by the invention has strong coordination with the phosphatidylserine on the surface of the cancer cell membrane, so that the metal cation compound can selectively act with the cancer cell membrane. Since phosphatidylserine is hardly present in the normal cell outer membrane, the metal cation compound can effectively adsorb a cancer cell membrane at a relatively low concentration. It disturbs the cell membrane structure of cancer cells due to the presence of hydrophobic structures, causing cell membrane lysis and physical damage. The metal cation compound has broad-spectrum anticancer property and does not generate drug resistance.
The metal cation compound designed by the invention can effectively kill cancer cells, selectively kill tumors, reduce the damage to normal cells, improve the anti-tumor effect and reduce the toxic and side effects. The metal cation compound can form nano micelle without a carrier, and realizes high enrichment of tumor parts through high permeability and retention effect of solid tumors and specific combination of the solid tumors. The amphiphilic micromolecule has a simple structure and a large clinical transformation potential. Compared with the traditional antitumor drug, the novel antitumor drug can play a role without entering cells, can not generate drug resistance, and can inhibit tumor metastasis.
Drawings
Figure 1 shows a schematic of the synthesis of a specific metal cation compound.
Fig. 2 shows the nmr hydrogen spectrum of the metal cation compound precursor in example 2.
Figure 3 shows the in vitro anti-tumor effect of metal cation compounds.
Fig. 4 shows a scanning electron micrograph of cancer cells after treatment with a metal cation compound.
Figure 5 shows the effect of resistance of metal cation compounds.
Fig. 6 shows the anti-tumor metastasis effect of metal cation compounds.
Figure 7 shows the in vivo anti-tumor effect of metal cation compounds.
Detailed Description
The invention is further illustrated with reference to examples and figures. The reagents used in the examples were purchased from national pharmaceutical group chemical agents, Inc., and the cells were purchased from Shanghai cell Bank of Chinese academy.
Example 1
A100 mL flask was charged with dodecanol (3.72g, 0.02mol) and triethylamine (2.02g, 0.02 mol). Acryloyl chloride (2.02g, 0.02mol) was dissolved in dichloromethane (50 mL). The acryloyl chloride solution was added to the reaction solution over 30 minutes using a constant pressure dropping funnel and allowed to stand overnight at 20 ℃. Washing the reaction solution for three times by pure water to remove most triethylamine hydrochloride, drying and concentrating, and purifying by a silica gel column (ethyl acetate/petroleum ether 10:1) to obtain the farnesyl acrylate.
The compound of formula III (n ═ 2) (0.726g, 0.003mol), tridecyl acrylate (2.40g, 0.01mol) and triethylamine (0.606g, 0.006mol) were added to 3.0mL of DMF and reacted at 90 ℃ for 48h in a sealed tube under an argon atmosphere. Separating with silica gel column (dichloromethane/methanol 10:1) to obtain metal cation compound precursor, wherein the nuclear magnetic resonance hydrogen spectrum is shown in FIG. 2.
The metal cation compound precursor (2.0g) was dissolved in methanol, an equal amount of nickel nitrate was added, stirred at room temperature for 4 hours, and dried to obtain the metal cation compound of formula V.
Figure BDA0002981678550000061
Example 2
In vitro antitumor evaluation of Metal cation Compounds
The in vitro anti-tumor effect of the metal cation compound is measured by adopting an MTT mode: cancer cells (HepG2) were pre-added to 96-well plates and cultured overnight. The metal cation compound (formula V) was configured to a concentration of 800. mu.M. The metal cation compound (formula V) forms nano-micelle with uniform size by observation of a transmission electron microscope. After culturing the cells in the presence of 10. mu.M to 100. mu.M of the metal cation compound (formula V) for 24 hours, the medium was aspirated. After 4 hours incubation with MTT, 100 microliters of dimethyl sulfoxide (DMSO) was added per well, which was able to dissolve formazan in the cells. The light absorption value of the sample is measured by an enzyme linked immunosorbent assay detector at the wavelength of 570nm, and the cytotoxicity of the sample corresponding to the sample is calculated by the ultraviolet absorption ratio of the sample to the PBS control group. Similar in vitro anti-tumor evaluations were performed in Hela, U373, CT-26, 3T3 and Mac cells. Figure 3 shows the in vitro anti-tumor effect in different cells. From the experimental results, it can be seen that the metal cation compound (formula V) can achieve excellent in vitro anti-tumor effects in various cancer cells, while having less cytotoxicity to normal cells such as 3T3 and Mac. In addition, the cells treated with the metal cation compound of formula V were observed by scanning electron microscopy, as shown in fig. 4; the electron microscope photograph shows that severe damage occurs to the cell membrane and a large number of apoptotic bodies appear in the visual field, which indicates that the metal cation compound of formula V can effectively destroy the cell membrane of cancer cells and make them apoptotic.
Example 3
Evaluation of drug resistance of Metal cation Compound
The evaluation of the resistance of metal cation compounds is carried out by repeated stimulation with low concentrations of the drug and then evaluating the change in cytotoxicity. Cells that were not drug-treated (HepG2) were considered first generation cells. After the first generation cell confluence was about fifty percent, it was treated with 20 micromolar metal cation compound (formula V). After the cells are full, the cells are digested and disbursed, and the operation is repeated for three times to obtain second-generation cells. And obtaining fifth generation cells through repeated drug stimulation, measuring the toxicity of the metal cation compound to each generation of cells through an MTT mode, and evaluating the change of the sensitivity of the tumor cells to the metal cation compound. Fig. 5 shows cell survival rates for various generations of cells. As can be seen from fig. 5, the cell survival rates of the respective cell generations at the same concentration are not very different, and the cancer cells do not develop resistance to repeated stimulation by the metal cation compound (formula V).
Example 4
Evaluation of anti-tumor metastasis of Metal cation Compound
The anti-tumor metastasis experiments were evaluated by cell (3T3 cell) scratch experiments. Appropriate cell concentrations were seeded in 6-well plates and, upon cell confluency, the culture wells were evenly streaked with a 200 microliter pipette, passing at least 5 lines per well. The cells were washed 3 times with PBS at the same time, 1% serum was added to the medium, and the extent of change in scratch width was observed with a microscope at various times and photographed. Fig. 6 shows scratch widths after treatment with PBS and a metal cation compound (formula V). It can be seen that the scratch was significantly wider after the treatment with the metal cation compound (formula V), showing a good anti-tumor metastasis effect.
Example 5
In vivo antitumor evaluation of Metal cation Compounds
Well-grown CT26 cells were prepared as a PBS suspension at a cell concentration of 107Individual cells/mL. The tumor cell solution was inoculated into 100. mu.l subcutaneously in mice. Treatment was initiated when the tumor volume in mice increased to 100 cubic millimeters with a therapeutic dose of 2.0mg/kg (subcutaneous or intravenous injection of the metal cation compound (formula V)) and was administered every two days for a total of 4 treatments. The experiment was terminated after 12 days from the start of treatment of the mice. During this period, the change in tumor volume was measured by a vernier caliper, and the tumor volume was calculated in a manner of V1/2 × a × b2(a is the long side at the time of tumor measurement, b is the short side at the time of tumor measurement), to evaluate the in vivo antitumor experiment of the metal cation compound. Fig. 7 shows the change in tumor volume after intratumoral injection and intravenous injection of the experimental group (metal cation compound of formula V) and the control group (oxaliplatin (O-LHP)). It can be seen that the tumor volume increases more slowly after the treatment with the metal cation compound (formula V) than oxaliplatin (O-LHP), a first-line anticancer drug used clinically, showing a good in vivo antitumor effect.

Claims (9)

1. A metal cation compound of the formula I,
Figure FDA0002981678540000011
wherein
M is a divalent metal;
n is an integer of 1 to 10;
x is independently selected from O, S and NH; and is
R is a hydrophobic chain hydrocarbon group.
2. The metal cation compound of claim 1, wherein the divalent metal comprises Zn, Ni, Cu, Fe, and Co.
3. The metal cation compound according to claim 1, wherein n is an integer of 1 to 5, preferably n is 2.
4. The metal cation compound of claim 1, wherein R is C1-20Chain hydrocarbon radicals, e.g. C1-16Chain hydrocarbon radicals, e.g. C1-12Chain hydrocarbon radicals, e.g. C1-6A chain hydrocarbon group;
preferably, R is C1-20Alkyl or alkenyl radicals, e.g. C1-16Alkyl or alkenyl radicals, e.g. C1-12Alkyl or alkenyl radicals, e.g. C1-6An alkyl or alkenyl group;
preferably, R is selected from:
Figure FDA0002981678540000012
5. a process for preparing metal cation compounds of formula I,
Figure FDA0002981678540000021
wherein
M is a divalent metal;
n is an integer of 1 to 10;
x is independently selected from O, S and NH; and is
R is a hydrophobic chain hydrocarbon group;
the method comprises the following steps:
(1) reacting acryloyl chloride with a compound of formula R-X-H in an organic solvent to obtain a compound of formula II
Figure FDA0002981678540000022
(2) Carrying out Michael addition on the compound of the formula II and the compound of the formula III in an organic solvent to obtain the compound of the formula IV
Figure FDA0002981678540000023
(3) Reacting the compound of formula IV with a divalent metal salt in an organic solvent to obtain the metal cation compound of formula I.
6. The method of claim 5, wherein the divalent metal comprises Zn, Ni, Cu, Fe, and Co; or
Preferably, n is an integer from 1 to 5, preferably n is 2; or
Preferably, R is C1-20Chain hydrocarbon radicals, e.g. C1-16Chain hydrocarbon radicals, e.g. C1-12Chain hydrocarbon radicals, e.g. C1-6A chain hydrocarbon group; or
Preferably, R is C1-20Alkyl or alkenyl radicals, e.g. C1-16Alkyl or alkenyl radicals, e.g. C1-12Alkyl or alkenyl radicals, e.g. C1-6An alkyl or alkenyl group; or
Preferably, R is selected from:
Figure FDA0002981678540000031
7. the method of claim 5, wherein the divalent metal salt comprises zinc salts, nickel salts copper salts, iron salts, and cobalt salts, preferably zinc nitrate, zinc sulfate, zinc acetate, zinc chloride, zinc bromide, nickel nitrate, nickel sulfate, nickel acetate, nickel chloride, nickel bromide, cobalt nitrate, cobalt sulfate, cobalt acetate, cobalt chloride, cobalt bromide, copper nitrate, copper sulfate, copper acetate, ferrous nitrate, ferrous sulfate, ferrous acetate, and any combination thereof; more preferably, the divalent metal salt is nickel nitrate, zinc nitrate, cobalt nitrate.
8. The process of claim 5, wherein the organic solvent in steps (1) to (3) is independently selected from the group consisting of dimethylsulfoxide, N-dimethylformamide, dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol, acetonitrile, and any combination thereof.
9. The process of claim 5, wherein the reaction in step (1) is carried out in the presence of triethylamine as an acid-binding agent; preferably, the reaction temperature in the step (1) is 20-30 ℃, and the reaction time is 4-12 hours; or
Wherein the reaction in step (2) is carried out in the presence of triethylamine and in an inert atmosphere; or
Wherein the reaction temperature in the step (2) is 90-110 ℃, and the reaction time is 24-48 hours; or
Wherein the reaction temperature in the step (3) is 20-30 ℃, and the reaction time is 4-12 hours.
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